title: Co-expression of HLA-B7 and HLA-B27 alleles is associated with B7-restricted immunodominant responses following influenza infection.
abstract: It is recognized that host response following viral infection is characterized by immunodominance, but deciphering the different factors contributing to immunodominance has proved a challenge due to concurrent expression of multiple MHC class I alleles. To address this, we generated H2-K(-/-)/D(-/-) double-knockout transgenic mice expressing either one or two human MHC-I alleles. We hypothesized that co-expression of different allele combinations figures critically in immunodominance and examined this in influenza-infected, double Tg MHC-I mice. In A2/B7 or A2/B27 mice, using ELISpot assays with the A2-restricted matrix I.58-66, the B7-restricted NP418-426 or the B27-restricted NP383-391 influenza A (flu) epitopes, we observed the expected recognition of both peptides for both alleles. In contrast, in flu-infected B7/B27 mice, a significantly reduced level of B27/NP383-restricted CTL response was detected while there was no change in the B7/NP418-restricted CTL response. Flu-specific tetramer studies revealed a partial deletion of Vβ8.1(+) NP383/B27-restricted CD8(+) T cells, and a diminished Vβ12(+) CD8(+) T-cell expansion in B7/B27 Tg mice. Using HLA Tg chimeric mice, we confirmed these findings. These findings shed light on the immune consequences of co-dominant expression of MHC-I alleles for host immune response to pathogens.
authors.affiliation: Division of Genetics and Development, Toronto Western Research Institute, Toronto, Ontario, Canada; Department of Immunology, Faculty of Medicine, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Akram
authors.forename: Robert D
authors.initials: RD
authors.lastname: Inman
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D015796:HLA-B27 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015793:HLA-B7 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D015796:HLA-B27 Antigen; D015793:HLA-B7 Antigen; D016056:Immunodominant Epitopes; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: HLA‐B7 and HLA‐B27; Immunodominance; Influenza A; Thymic selection